1. Field of the Invention
The present invention relates to androgenic steroid compounds and a method of making and using the same.
2. Discussion of the Background
Testosterone is the principal male hormone and is required for the development and maintenance of secondary sexual characteristics, libido and spermatogenesis. Testosterone also has anabolic properties, in promoting in muscle growth and maintenance. Lower than normal testosterone levels in men have been associated with low energy, frailty, depression, decreased libido, weakness, lethargy, loss of lean body and bone mass and impotence. A second androgen, dihydrotestosterone (DHT), is produced from testosterone. DHT is a potent androgen. It is believed to be responsible for prostate growth and inhibitors of the enzyme that forms it have been used to treat prostatic hypertrophy and benign prostate hyperplasia.
Testosterone is rapidly metabolized in the body. Since the liver metabolizes most orally administered testosterone before it reaches the systemic blood circulation, large oral doses are necessary in order to have the desired effect. To some extent, this difficulty may be overcome by using the drug in the form of a fatty acid ester and administering the same by intramuscular injection, nevertheless, doses of 200 mg must still be given at weekly or bi-weekly intervals. Although testosterone can be administered by skin patch, large patches must be used due to low activity and rapid metabolism. Recently, a permeation-enhanced back patch was reported, however, this still requires the use of two large, i.e. 37 cm2 patches for a total area of 11.5 in2 or about 30% more area than an ordinary playing card.
Hence, a need exists for an androgenic compound that has enhanced potency relative to testosterone, which would permit more facile procedures for administration, such as the use of smaller skin patches, implantable devices or even oral or buccal administration.
In accordance with the present invention, androgenic steroid compounds are provided which exhibit enhanced activity relative to testosterone.
The present invention also provides a method of making the androgenic steroid compounds.
The present invention also provides a therapeutic method for the administration of the present androgenic steroid compounds and compositions containing the same.
Accordingly, the above objectives and others are provided by an androgenic steroid compound having the ring numbering system and the formula (I): 
wherein R1 is H or lower alkyl;
Yxe2x80x94Z is CHxe2x95x90C or CH2xe2x80x94CH, wherein H is xcex1 to the rings, or Yxe2x80x94CH wherein H is xcex1 to the rings and Y is S, O, or NR10, wherein R10 is H or lower alkyl;
R2 is an xcex1-substituent which is unsubstituted lower alkyl or fluoro-substituted lower alkyl;
R3 is C1-C8 alkyl, or C2-C8 alkenyl or alkynyl, which are optionally substituted; or R3 is C4-C8 cycloalkyl which is unsubstituted or substituted; or R3 is C6-C18 aryl which is unsubstituted or substituted; or R3 is a 5- to 15-membered heterocycle which is unsubstituted or substituted, and further wherein any of the above may be substituted with 1 to 3 heteroatoms or 1 to 5 halogen atoms or both; or
R3 is H or an acyl group (CO)xe2x80x94R4, wherein R4 is C1-C18 alkyl, or C2-C18 alkenyl or alkynyl which are optionally substituted; or R4 is C4-C18 cycloalkyl or substituted cycloalkyl; or R4 is C6-C18 aryl or substituted aryl; or R4 is a 5- to 15-membered heterocycle or substituted heterocycle, and wherein R4 may be optionally substituted with 1 to 3 heteroatoms or 1 to 5 halogen atoms or both;
R5 is xcex1-H, and R6 is xcex2-lower alkyl, alkenyl or alkynyl which are optionally substituted; or R5R6 is xe2x95x90CH2; and
X is O, H2, (H, OH) or (H1, OCOR4), wherein R4 is as defined above; or X is (H, OR3), wherein R3 is as defined above; or X is NOR7, wherein R7 is H or C1-C8 alkyl, or C2-C8 alkenyl or alkynyl which are optionally substituted; or R7 is C4-C8 cycloalkyl or substituted cycloalkyl; or R7 is C6-C18 aryl or substituted aryl; or R7 is a 5- to 15-membered heterocycle or substituted heterocycle, and R7 may be optionally substituted with 1 to 3 heteroatoms or 1 to 5 halogen atoms or both; or X is (OR8, OR9), where R8 and R9 are lower alkyl or (OR8, OR9) is a cyclic structure containing 2 to 3 carbon atoms, optionally substituted with lower alkyl, or 1 or 2 heteroatoms or halogens.
In accordance with the present invention, certain androgenic steroid compounds are provided which exhibit surprisingly enhanced activity relative to testosterone. Due to the enhanced potency of the present compounds, their administration is quite facile. For example, by virtue of the present invention, it is now possible to significantly reduce the size of skin patches required for skin administration. This also provides greater flexibility in the design of the patches. Moreover, the compounds of the present invention exhibit long-lasting effects after injection.
Generally, the present invention provides androgenic steroid compounds of the formula (I): 
wherein:
R1 is H or lower alkyl;
Yxe2x80x94Z is CHxe2x95x90C or CH2xe2x80x94CH, wherein H is xcex1 to the rings; or Yxe2x80x94CH wherein H is xcex1 to the rings and Y is S, O, or NR10, wherein R10 is H or lower alkyl;
R2 is an xcex1-substituent which is unsubstituted lower alkyl or fluoro-substituted lower alkyl;
R3 is C1-C8 alkyl, or C2-C8 alkenyl or alkynyl which are optionally substituted; or R3 is C4-C8 cycloalkyl which is unsubstituted or substituted; or R3 is C6-C18 aryl which is unsubstituted or substituted; or R3 is a 5- to 15-membered heterocycle which is unsubstituted or substituted, and further wherein any of the above may be further substituted with 1 to 3 heteroatoms or 1 to 5 halogen atoms or both; or
R3 is H or an acyl group (CO)xe2x80x94R4, wherein R4 is C1-C18alkyl, or C2-C18 alkenyl or alkynyl which are optionally substituted; or R4 is C4-C18 cycloalkyl or substituted cycloalkyl; or R4 is C6-C18 aryl or substituted aryl; or R4 is a 5- to 15-membered heterocycle or substituted heterocycle, and wherein R4 may be optionally substituted with 1 to 3 heteroatoms or 1 to 5 halogen atoms or both;
R5 is xcex1-H, and R6 is xcex2-lower alkyl, alkenyl or alkynyl which are optionally substituted; or R5R6 is xe2x95x90CH2; and
X is O, H2, (H, OH) or (H, OCOR4), wherein R4 is as defined above, or X is (H, OR3), wherein R3 is as defined above; or X is NOR7, wherein R7 is H or C1-C8 alkyl or C2-C8 alkenyl or alkynyl, optionally substituted; or R7 is C4-C8 cycloalkyl which is unsubstituted or which is unsubstituted or substituted, and R7 may be optionally substituted with 1 to 3 heteroatoms or 1 to 5 halogen atoms or both; or X is (OR8, OR9), where R8 and R9 are lower alkyl, or (OR8, OR9) is a cyclic structure containing 2 to 3 carbon atoms, optionally substituted with lower alkyl, or 1 to 2 heteroatoms or halogen atoms or both.
In the above formula, it is preferred that R1 is H, R2 is CH3, R3 is H, or is an acyl group of the formula R4(CO), wherein R4 is CH3, C2H5, n-C6H13, (CH3)2CH, cyclopentyl-CH2xe2x80x94CH2, trans-(4-n-butyl)cyclohexyl, n-C9H19, (CH2)2(CO)(CH2)5CH3, phenyl-CH2 or 3-pyridyl, or R3 is CH3, C2H5, CH2OCH3, Si(CH3)3, CCl3xe2x80x94CH(OH), or 2-tetrahydropyranyl; R5 is xcex1-H and R6 is xcex2-CH3 or R5R6 is xe2x95x90CH2; and X is O, NOH or NOCH3.
More preferably, compounds, such as 7xcex1,11xcex2-dimethyl-17xcex2-hydroxyestr-4-en-3-one, 17xcex2-hydroxy-7xcex1-methyl-11-methyleneestr-4-en-3-one, 7xcex1,11xcex2-dimethyl-17xcex2-heptanoyl-oxyestr-4-en-3-one, 7xcex1,11xcex2-dimethyl-17xcex2-[[(2-cyclopentylethyl)carbonyl]oxy]estr-4-en-3-one, 7xcex1,11xcex2-dimethyl-17xcex2-(phenacetyloxy)estr-4-en-3-one, 7xcex1,11xcex2-dimethyl-17xcex2-[[(trans-4-(n-butyl)cyclohexyl)carbonyl]oxy]estr-4-en-3-one, and 7xcex1,11xcex2-dimethyl-17xcex2-hydroxy-5xcex1-estran-3-one may be mentioned.
As used herein, the terms xe2x80x9clower alkylxe2x80x9d and xe2x80x9clower alkoxyxe2x80x9d mean from 1 to 8 carbons, preferably from 1 to 4 carbons and specifically methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl. The term xe2x80x9ccycloalkylxe2x80x9d means a cyclic structure which may have one or more rings, fused or unfused, each ring containing 4 to 12 carbon atoms, and optionally containing double bond unsaturation. For example, single rings may include from 4 to 12 carbons, such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, or cyclododecyl.
The term xe2x80x9cheteroatomxe2x80x9d means oxygen, nitrogen, sulfur or silicon atoms.
Further, where used the term xe2x80x9csubstitutedxe2x80x9d generally means substituted with lower alkyl or alkoxy as defined herein, and preferably with 1 to 4 carbons, or with halogen, such as fluoro or with both.
As used herein, the terms xe2x80x9clower alkenylxe2x80x9d and xe2x80x9clower alkynylxe2x80x9d mean, in general, those groups with 2 to 8, preferably 1 to 4, carbons. Examples of xe2x80x9clower alkenylxe2x80x9d are vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl or octenyl. Examples of xe2x80x9clower alkynylxe2x80x9d are ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl or octynyl.
Additionally, as used herein, xe2x80x9cheterocyclexe2x80x9d means any heterocyclic ring system containing 1 to 3 heteroatoms, such as pyrazine, pyrimidine, pyridazine, imidazole, isoxazoline, pyrazole, pyrazolidine or thiazoline. By 5- to 15-membered is meant that the total number of structural core atoms in the ring system is 5- to 15. This includes carbon atoms and the heteroatoms in the ring system, and substituents, and not, of course, hydrogen. Furthermore, the ring system may consist of a single ring, as exemplified above, or may consist of fused ring systems, such as, for example, quinoline, or multiple unfused rings, such as, for example, 2-phenylpyridine.
As may be seen from the formula above, the androgenic steroid compounds of the present invention generally contain a 7xcex1-group in conjunction with an 11xcex2-methyl group or an 11-methylene group. Generally, moieties R1 and xe2x80x94OR3 of formula (I) are each in the xcex2-orientation.
Further, the present compounds are generally characterized by a 17xcex2-hydroxyl, ether or ester group. Generally, the 17xcex2-ester or ether compounds may be considered to be pro-drugs of the 17xcex2-hydroxy compounds. The former are presumably metabolized or hydrolyzed in vivo to form the latter.
Moreover, the present compounds are further generally characterized by a 3-keto, -oxime or -methoxime group.
Generally, R2 is lower alkyl or lower alkyl substituted by fluorine.
R3 is H or an acyl group (CO)xe2x80x94R4, wherein R4 is C1-C18 alkyl, or C2-C13 alkenyl or alkynyl which are optionally substituted; or R4 is C4-C18 cycloalkyl or substituted cycloallyl; or
R4 is C4-C18 aryl or substituted aryl; or R4 is a 5- to 15-membered heterocycle or substituted heterocycle, and wherein each of the above may be optionally substituted with 1 to 3 heteroatoms or 1 to 5 halogen atoms or both; or
R6 is lower alkyl, lower alkenyl or lower alkynyl.
X is O, H2, (H, OH) or (H, OCOR4), wherein R4 is as defined above; or X is (H, OR3), wherein R3 is as defined above; or X is NOR7, wherein R7 is H or C1-C8 alkyl, or C2-C18 alkenyl or alkynyl which are optionally substituted; or R7 is C4-C8 cycloalkyl or substituted cycloalkyl; or R7 is C6-C18 aryl or substituted aryl; or R7 is a 5- to 15-membered heterocycle or substituted heteorcycle, and R7 may be optionally substituted with 1 to 3 heteroatoms or 1 to 5 halogen atoms or both; or X is (OR8, OR9), wherein R8 and R9 are lower alkyl, or (OR8, OR9) is a cyclic structure containing 2 to 3 carbon atoms, optionally substituted with lower alkyl groups, or 1 or 2 heteroatoms or halogens.
For example, (OR8, OR9) may be a cyclic group to form, with the C-3 carbon atom, a ketal, such as from ethylene glycol or 2,2-dimethyl propane-1,3-diol.
Examples of R3 being (CO)xe2x80x94R4, when R4 is C1-C18 alkyl, or C2-C18, alkenyl or alkynyl which are optionally substituted and which may be (CO)xe2x80x94CH3, (CO)xe2x80x94C2H5, (CO)xe2x80x94C3H7, (CO)xe2x80x94C4H9, (CO)xe2x80x94C5H11, (CO)xe2x80x94C6H13 or (CO)xe2x80x94C7H15, (CO)xe2x80x94C8H17, for alkyl, for example; (CO)xe2x80x94CH2xe2x80x94CHxe2x95x90CH2, (CO)xe2x80x94CHxe2x95x90CHxe2x80x94CH3, (CO)xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH3, (CO)xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH3, (CO)xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH3, (CO)xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)2xe2x80x94CH3 or (CO)xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)3xe2x80x94CH3 for alkenyl, for example; and (CO)xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, (CO)xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, (CO)xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2Cxe2x89xa1Cxe2x80x94CH3, for alkynyl, for example.
Generally, substituted cycloalkyl, consistent with the above definition of xe2x80x9csubstitutedxe2x80x9d is cycloalkyl substituted by lower alkyl, lower alkoxy or halogen, preferably fluoro.
Moreover, as used herein xe2x80x9carylxe2x80x9d means carbocyclic aromatic groups, such as phenyl or naphthyl, for example, having up to 18 carbons.
Synthesis of the Androgenic Steroid Compounds
The androgenic steroid compounds of the present invention may be prepared using known reagents and reactions.
The following preparatory scheme is exemplary and provided for purposes of illustration and is not intended to be limitative.